Mediators released from LPS-challenged lungs induce inflammatory responses in liver vascular endothelial cells and neutrophilic leukocytes

doi:10.1152/ajpgi.00278.2009

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Mediators released from LPS-challenged lungs induce inflammatory responses in liver vascular endothelial cells and neutrophilic leukocytes

N. Markovic,¹ L. A. McCaig,² J. Stephen,¹ S. Mizuguchi,¹ R. A. W. Veldhuizen,¹^,2 J. F. Lewis,¹^,2 and G. Cepinskas¹^,2^,3

Centre for Critical Illness Research, Lawson Health Research Institute and Departments of ¹ Physiology and Pharmacology, ²Medicine, and ³Medical Biophysics, University of Western Ontario, London, Ontario, Canada

Submitted July 14, 2009 ; accepted in final form October 5, 2009

The systemic inflammatory response plays an important role inthe progression of acute lung injury (ALI) to multiple organdysfunction syndrome (MODS). However, the role of lung-derivedinflammatory mediators in induction of the inflammatory responsein remote organs is poorly understood. To address the above,we investigated the effects of lung inflammation on inductionof inflammatory response(s) in the liver in vitro. Inflammationin mouse lungs was induced by intranasal administration of lipopolysaccharide(LPS; 1 mg/ml) followed by mechanical ventilation using theisolated perfused mouse lung method to obtain and characterizelung perfusate from the pulmonary circulation. LPS administrationto mouse lungs resulted in an increased release of inflammation-relevantcytokines and chemokines into the perfusate (Luminex assay)compared with the saline-controls. Subsequently, primary mouseliver vascular endothelial cells (LVEC) or mouse polymorphonuclearleukocytes (PMN) in vitro were stimulated with the perfusateobtained from saline- or LPS-challenged lungs and assessed forvarious inflammation-relevant end points. The obtained resultsindicate that stimulation of LVEC with perfusate obtained fromLPS-challenged lungs results in 1) reactive oxygen species (ROS)production; 2) activation of NF- ${kappa}$ B; and 3) expression of E-selectin,ICAM-1, and VCAM-1 and a subsequent increase in PMN rollingand adhesion to LVEC. In addition, perfusate from LPS-challengedlung induced activation of PMN with respect to increased ROSproduction and upregulation of cell surface levels of adhesionmolecules MAC-1 and VLA-4. Heat-inactivation of the perfusateobtained from LPS-challenged lungs was very effective in suppressingincreased proadhesive phenotype (i.e., E-selectin and ICAM-1expression) in LVEC, whereas targeted inhibition (immunoneutralization)of TNF- ${alpha}$ and/or IL-6 in LPS-lung perfusate had no effect. Takentogether, these findings indicate that multiple proinflammatorymediators (proteinaceous in nature) released from inflamed lungsact synergistically to induce systemic activation of circulatingPMN and promote inflammatory responses in liver vascular endothelialcells.

acute lung injury; pulmonary inflammation; systemic inflammation; isolated perfused mouse lung

Address for reprint requests and other correspondence: G. Cepinskas, Centre for Critical Illness Research, Lawson Health Research Institute, 800 Commissioners Rd. East, VRL, 6th Floor, Rm. A6-136, London, ON, Canada, N6A 4G4 (e-mail: gcepinsk{at}uwo.ca).